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Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism.

Wills S, Rossi CC, Bennett J, Martinez Cerdeño V, Ashwood P, Amaral DG, Van de Water J - Mol Autism (2011)

Bottom Line: Autoantibody-positive cells rarely expressed calretinin.Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510 GBSF, Davis, CA 95616, USA. javandewater@ucdavis.edu.

ABSTRACT

Background: Autism is a neurodevelopmental disorder characterized by impairments in social interaction and deficits in verbal and nonverbal communication, together with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes of autism are currently unclear. In a previous study, we determined that 21% of children with autism have plasma autoantibodies that are immunoreactive with a population of neurons in the cerebellum that appear to be Golgi cells, which are GABAergic interneurons.

Methods: We have extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double-labeling studies that included one of the calcium-binding proteins that are commonly colocalized in GABAergic neurons (calbindin, parvalbumin or calretinin) were also carried out to determine which GABAergic neurons are immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were reacted with plasma from each of seven individuals with autism who had previously demonstrated positive Golgi cell staining, as well as six negative controls. In addition, brain sections from adult male mice were similarly examined.

Results: In each case, specific staining was observed for neurons that had the morphological appearance of interneurons. By double-labeling sections with plasma and with antibodies directed against γ-aminobutyric acid (GABA), we determined that all autoantibody-positive neurons were GABAergic. However, not all GABAergic neurons were autoantibody-positive. Calbindin was colabeled in several of the autoantibody-labeled cells, while parvalbumin colabeling was less frequently observed. Autoantibody-positive cells rarely expressed calretinin. Sections from the mouse brain processed similarly to the primate sections also demonstrated immunoreactivity to interneurons distributed throughout the neocortex and many subcortical regions. Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.

Conclusions: These results suggest that the earlier report of autoantibody immunoreactivity to specific cells in the cerebellum extend to other regions of the brain. Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons. The potential impact of these autoantibodies on GABAergic disruption with respect to the etiology of autism is discussed herein.

No MeSH data available.


Related in: MedlinePlus

Photomicrographs of the caudate nucleus of the macaque monkey. (A) Nissl-stained section showing the density of striatal neurons in this region. (B) Phase-contrast photomicrograph illustrating small (approximately 10 μm in diameter), stellate neurons stained with plasma from a representative AU subject. (C) Section though the caudate nucleus reacted with a monoclonal antibody to GABA. Immunoreactivity is associated with numerous axonal varicosities as well as a variety of neuronal cell types. The small, stellate cell type observed by plasma immunohistochemical staining is also shown in the GABA preparations (black arrow). Other, larger GABAergic neurons (white arrow) can also be observed. Calibration bar, 10/100 μm.
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Figure 8: Photomicrographs of the caudate nucleus of the macaque monkey. (A) Nissl-stained section showing the density of striatal neurons in this region. (B) Phase-contrast photomicrograph illustrating small (approximately 10 μm in diameter), stellate neurons stained with plasma from a representative AU subject. (C) Section though the caudate nucleus reacted with a monoclonal antibody to GABA. Immunoreactivity is associated with numerous axonal varicosities as well as a variety of neuronal cell types. The small, stellate cell type observed by plasma immunohistochemical staining is also shown in the GABA preparations (black arrow). Other, larger GABAergic neurons (white arrow) can also be observed. Calibration bar, 10/100 μm.

Mentions: We also observed autoantibody labeling within the caudate nucleus of the striatum (Figure 8), although there were very few labeled neurons in this region. All of the positively labeled cells were small (approximately 8 to 10 μm in diameter), with round cell bodies and short dendrites radiating in all directions (Figure 8B). When we examined sections stained immunohistochemically with an antibody to GABA (Figure 8C), it was clear that the autoantibody-labeled neurons resembled one of the classes of neurons demonstrating GABA immunoreactivity (Figure 8C). However, larger GABA-immunoreactive neurons that were not stained with the autoantibodies were also present.


Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism.

Wills S, Rossi CC, Bennett J, Martinez Cerdeño V, Ashwood P, Amaral DG, Van de Water J - Mol Autism (2011)

Photomicrographs of the caudate nucleus of the macaque monkey. (A) Nissl-stained section showing the density of striatal neurons in this region. (B) Phase-contrast photomicrograph illustrating small (approximately 10 μm in diameter), stellate neurons stained with plasma from a representative AU subject. (C) Section though the caudate nucleus reacted with a monoclonal antibody to GABA. Immunoreactivity is associated with numerous axonal varicosities as well as a variety of neuronal cell types. The small, stellate cell type observed by plasma immunohistochemical staining is also shown in the GABA preparations (black arrow). Other, larger GABAergic neurons (white arrow) can also be observed. Calibration bar, 10/100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3108923&req=5

Figure 8: Photomicrographs of the caudate nucleus of the macaque monkey. (A) Nissl-stained section showing the density of striatal neurons in this region. (B) Phase-contrast photomicrograph illustrating small (approximately 10 μm in diameter), stellate neurons stained with plasma from a representative AU subject. (C) Section though the caudate nucleus reacted with a monoclonal antibody to GABA. Immunoreactivity is associated with numerous axonal varicosities as well as a variety of neuronal cell types. The small, stellate cell type observed by plasma immunohistochemical staining is also shown in the GABA preparations (black arrow). Other, larger GABAergic neurons (white arrow) can also be observed. Calibration bar, 10/100 μm.
Mentions: We also observed autoantibody labeling within the caudate nucleus of the striatum (Figure 8), although there were very few labeled neurons in this region. All of the positively labeled cells were small (approximately 8 to 10 μm in diameter), with round cell bodies and short dendrites radiating in all directions (Figure 8B). When we examined sections stained immunohistochemically with an antibody to GABA (Figure 8C), it was clear that the autoantibody-labeled neurons resembled one of the classes of neurons demonstrating GABA immunoreactivity (Figure 8C). However, larger GABA-immunoreactive neurons that were not stained with the autoantibodies were also present.

Bottom Line: Autoantibody-positive cells rarely expressed calretinin.Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510 GBSF, Davis, CA 95616, USA. javandewater@ucdavis.edu.

ABSTRACT

Background: Autism is a neurodevelopmental disorder characterized by impairments in social interaction and deficits in verbal and nonverbal communication, together with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes of autism are currently unclear. In a previous study, we determined that 21% of children with autism have plasma autoantibodies that are immunoreactive with a population of neurons in the cerebellum that appear to be Golgi cells, which are GABAergic interneurons.

Methods: We have extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double-labeling studies that included one of the calcium-binding proteins that are commonly colocalized in GABAergic neurons (calbindin, parvalbumin or calretinin) were also carried out to determine which GABAergic neurons are immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were reacted with plasma from each of seven individuals with autism who had previously demonstrated positive Golgi cell staining, as well as six negative controls. In addition, brain sections from adult male mice were similarly examined.

Results: In each case, specific staining was observed for neurons that had the morphological appearance of interneurons. By double-labeling sections with plasma and with antibodies directed against γ-aminobutyric acid (GABA), we determined that all autoantibody-positive neurons were GABAergic. However, not all GABAergic neurons were autoantibody-positive. Calbindin was colabeled in several of the autoantibody-labeled cells, while parvalbumin colabeling was less frequently observed. Autoantibody-positive cells rarely expressed calretinin. Sections from the mouse brain processed similarly to the primate sections also demonstrated immunoreactivity to interneurons distributed throughout the neocortex and many subcortical regions. Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.

Conclusions: These results suggest that the earlier report of autoantibody immunoreactivity to specific cells in the cerebellum extend to other regions of the brain. Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons. The potential impact of these autoantibodies on GABAergic disruption with respect to the etiology of autism is discussed herein.

No MeSH data available.


Related in: MedlinePlus